Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
  • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties

Definitions

• This invention relates to a process for preparing 6-alkoxytetralones.
• 6-alkoxytetralones are useful as chemical intermediates, especially as pharmaceutical intermediates, and that they can be prepared in various ways. As taught by Stork, Journal of the American Chemical Society , Vol. 69, pp. 576-579 (1947), Thomas et al., Journal of the American Chemical Society , Vol. 70, pp. 331-334 (1948), and Bhatt et al., Tetrahedron Letters , Vol. 22, pp. 2605-2608 (1981), the 6-alkoxytetralones can be prepared by the oxidation of 6-alkoxytetralins, but these known oxidation techniques have not proved to be commercially attractive.
• An object of this invention is to provide a novel process for preparing 6-alkoxytetralones wherein the 6-alkoxytetralones are prepared from 6-alkoxytetralins.
• a further object is to provide such a process which is commercially attractive.
• a process which comprises heating a mixture of (A) a 6-alkoxytetralin, (B) a sulfate, nitrate, or halide salt of bivalent titanium, vanadium, chromium, manganese, iron, cobalt, nickel, or copper, and (C) a tertiary amine having a pKa value of at least about 5.23 to a temperature not higher than about 100°C, gradually adding (a) an ammonium or alkali metal persulfate to the reaction mixture, and maintaining the 6-alkoxytetralin in intimate contact with the persulfate so as to oxidize it to a 6-alkoxytetralone.
• the 6-alkoxytetralin that is oxidized in the process of the invention may be any 6-alkoxytetralin but is generally a 6-alkoxytetralin wherein the alkoxy group contains 1-20, preferably 1-6 carbons, such as the 6-alkoxytetralins wherein the alkoxy group is methoxy, ethoxy, 1-methylethoxy, butoxy, hexoxy, etc.
• a particularly preferred 6-alkoxytetralin is 6-methoxytetralin.
• these compounds when not commercially available, can be prepared by the catalytic hydrogenation of the appropriate 6-alkoxynaphthalene, by the sulfonation, alkali fusion, and alkylation of tetralin, or by the catalytic hydrogenation of the appropriate 7-alkoxytetralone.
• the synthesis is most conveniently accomplished by reacting 6-hydroxytetralin with sodium hydroxide and then with a suitable alkylating agent, such as the appropriate alkyl halide or dialkyl sulfate.
• the salt employed in the process of the invention is a catalyst and is a sulfate, nitrate, or halide salt of of titanium, vanadium, chromium, manganese, iron, cobalt, nickel, or copper, but it is preferably cupric or ferrous sulfate, most preferably cupric sulfate.
• the amount of salt employed is generally in the range of 0.1-1.2 mols, preferably about one mol, per mol of 6-alkoxytetralin.
• the tertiary amine used in the process is an ingredient that improves the yield of product, its efficacy generally increasing with increased basicity.
• it is a tertiary amine having a pKa value of at least about 5.23, preferably at least about 6.62, as determined by a method generally in accordance with the method taught in Gero et al., Journal of Organic Chemistry , Vol. 16, pp. 1835-1838 (1951).
• amines are trialkylamines, such as trimethyl, triethyl, tripropyl, etc., amines; pyridines, such as pyridine, the 2- and 4-methylpyridines, the 2,4- and 2,6-dimethylpyridines, 2,4,6-trimethylpyridine, the corresponding alkylpyridines wherein the alkyl groups are ethyl, propyl, etc., 2-methyl-5-ethylpyridine, etc.
• the preferred tertiary amines are pyridines, especially alkylpyridines, and most especially alkylpyridines having a pka value of at least about 6.62. This yield improver is typically employed so as to provide 0.5-6, preferably 2-5, mols of amine per mol of 6-alkoxytetralin.
• the oxidizing agent of the process is ammonium persulfate or any alkali metal persulfate, However, as a practical matter, it is preferred to use sodium, potassium, or ammonium persulfate; and sodium persulfate is particularly preferred.
• the amount of persulfate employed is usually 2-4 mols per mol of 6-alkoxytetralin.
• the 6-alkoxytetralin, salt, and tertiary amine are mixed with one another and brought to the desired reaction temperature prior to the addition of the persulfate.
• This reaction temperature can be any temperature between about room temperature and about 100°C , but it is preferably in the range of 65-70°C because of the higher yields obtained at such reaction temperatures.
• the persulfate is gradually added to the other ingredients so as to achieve an intimate admixture and permit the attainment of higher product yields than can be obtained when the reaction ingredients are brought together more abruptly, e.g., as in Bhatt et al.
• the achievement of an intimate admixture is facilitated by the use of stirring, and it is also efficacious to solubilize or disperse the reaction ingredients in suitable media prior to the addition of the persulfate.
• solubilization or dispersion of the reaction ingredients is generally achieved by dissolving or dispersing the 6-alkoxytetralin, salt, and tertiary amine in a suitable inert organic solvent, such as acetonitrile, propionitrile, acetone, methanol or other lower alcohol, etc., and/or dissolving the persulfate in water. It is most efficacious to dissolve or disperse both sets of ingredients, i.e., the tetralin, salt and amine as one set and the persulfate as the other.
• a suitable inert organic solvent such as acetonitrile, propionitrile, acetone, methanol or other lower alcohol, etc.
• the persulfate After the persulfate has been added, it is maintained in intimate admixture with the 6-alkoxytetralin for a suitable time, e.g., 1-5 hours when the preferred temperatures are used, to oxidize the tetralin to the corresponding tetralone.
• the 6-alkoxytetralone can then be recovered by conventional techniques.
• the invention is advantageous in that it provides a commercially attractive process capable of producing 6-alkoxytetralones in high yields. It also has the advantage of permitting the use of crude 6-alkoxytetralins containing the 3-alkoxytetralins which are formed as by-products in the 6-alkoxytetralin synthesis and which are difficult to separate therefrom.
• the 3-alkoxytetralin impurity is an inert ingredient and is easily separated from the 6-alkoxytetralone product by distillation.
• reaction mixture was then cooled to 25°C , and the solid was filtered off and rinsed three times with toluene, after which the filtrate was washed with water. HPLC analysis of the toluene layer showed that the yield of 6-methoxytetralone was 92.2%.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 1985
  • 1985-06-10 US US06/742,881 patent/US4603221A/en not_active Expired - Fee Related
• 1986
  • 1986-05-07 CA CA000508566A patent/CA1243688A/en not_active Expired
  • 1986-05-12 EP EP86106408A patent/EP0204975B1/en not_active Expired - Lifetime
  • 1986-05-12 DE DE8686106408T patent/DE3680244D1/de not_active Expired - Fee Related
  • 1986-05-12 AT AT86106408T patent/ATE65239T1/de not_active IP Right Cessation
  • 1986-06-10 JP JP61134721A patent/JPS6236339A/ja active Granted

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